In this project, I will investigate the role of inhibitory synapses on VTA dopamine neurons in animal models of stress and depression. Dopamine neurons of the ventral tegmental area are a crucial part of the brain's reward processing system, and function of these neurons is greatly influenced by both acute and chronic stress. Inhibitory synapses onto dopamine neurons powerfully modulate their activity, and are thus poised to be a significant mediator of stress's effects on the VTA. In this proposal, I will take a multidisciplinry approach to address the hypothesis that inhibitory synapses in the VTA are a key locus for the effects of stress on the brain and a determinant of susceptibility in an animal model of chronic social stress. During the mentored K99 phase, I will first determine the cellular signaling components that contribute to long-lasting stress-induced deficits in inhibitory synaptic plasticit after an acute stressor. Second, I will utilize optogenetic techniques to test the stress-sensitiviy of specific inhibitory inputs on dopamine neurons, including those from GABAergic interneurons within the VTA as well as from other brain regions. During the independent R00 phase, I will utilize the chronic social defeat model of susceptibility to stress-induced depressive behavior to investigate the role of inhibitory synapses on VTA dopamine neurons in stress susceptibility. In this phase, I will study inhibitory synapses onto two distinct subsets of dopamine neurons, those projecting to the nucleus accumbens and those projecting to the prefrontal cortex, in animals that show differential behavioral responses to social defeat. These studies hold the potential to contribute significantly to our understanding of how the reward system is altered by stress and may lead to novel avenues for the development of therapeutic treatments for depression and other stress-linked disorders. My long term career goal is to become an independent investigator at an academic institution where I will establish a research program investigating synaptic and circuit level mechanisms of mental illness. Such a position will give me the opportunity to combine my interests in research, mentoring, and teaching. My graduate and postdoctoral training has given me a strong conceptual framework in the neuroscience of mental illness and provided me with a set of behavioral, biochemical, and electrophysiological skills. The training plan outlined in this proposal will allow me to continue to broaden my technical and intellectual expertise while gaining professional skills that will help me successfully obtain a faculty position and establish an innovative research program. During the K99 phase, I will receive training from my mentor, Dr. Julie Kauer, and my co-mentors, Dr. Chris Moore, Dr. Kevin Bath, and Dr. Scott Russo. Under their guidance, I will learn to use optogenetic techniques and the chronic social defeat stress behavioral paradigm. In addition, my training will be enhanced by the supportive and collegial neuroscience research community and the many professional development opportunities at Brown University. The support of my mentoring team and the exceptional training environment at Brown University will facilitate my transition to an independent position.